The 13-cis isomer of retinoic acid (2Z, 4E, 6E, 8E)-3,7-dimethyl-9(2,6,6-trimethylcyclohex-1-enyl)nona-2,4,6,8-tetraenoic acid, otherwise known as isotretinoin, is a valuable pharmaceutical that is used to treat acne. Many methods for synthesizing isotretinoin are known in the art. U.S. Pat. No. 4,556,518 (the '518 patent) describes a process for producing isotretinoin according to the following reaction scheme: ##STR1##
The first step of the reaction involves reacting a Wittig salt having the formula I with a butenolide having the formula II at a temperature of from about -10.degree. to -50.degree. C. in the presence of a strong base, such as a hydroxide or alkoxide, and an organic solvent. As shown above, the reaction of the Wittig salt having formula I and the butenolide of formula II produce compounds having the formula III and IV. The major product is the 11-cis isomer (formula III). In order to produce 13-cis retinoic acid as the major product, the compound having formula III is isomerized to produce a compound having formula IV. The isomerization reaction is carried out by treating the compound having formula III with a catalyst in an inert solvent medium. The catalyst is typically a compound or complex of palladium or rhodium. The catalyst selectively isomerizes the 11-cis double bond in the compound having formula III to the corresponding trans double bond without affecting the 13-cis double bond in order to produce a compound having the formula IV.
Therefore, there is a need in the art for a process of producing isotretinoin under moderate conditions that does not employ toxic heavy metals.
There are several difficulties associated with the reaction described in the '518 patent. First, palladium and rhodium are heavy metals which are toxic. It is also difficult to reduce the amounts of these heavy metals in the final product to an acceptable level. Moreover, the preferred temperature for the Wittig reaction is -25.degree. C. or below which would necessitate the use of special equipment for commercial preparation.
U.S. Pat. No. 5,424,465 describes the use of irradiation in an organic solvent in the presence of a suitable photosensitizer to influence the isomerization of the 11-cis isomer to the 11-trans isomer. Disadvantages of this process include, having to recycle mother liquors to affect complete photoisomerization, the use of special equipment, and the removal of residual photosensitizer from the final product.